2. Academic Validation
  3. Conductive coordination nanozyme prodrugs precisely trigger pyroptosis, cuproptosis and ferroptosis for in situ cancer vaccination

Conductive coordination nanozyme prodrugs precisely trigger pyroptosis, cuproptosis and ferroptosis for in situ cancer vaccination

  • Signal Transduct Target Ther. 2026 Mar 16;11(1):96. doi: 10.1038/s41392-026-02607-6.
Yuqiao Wang # 1,  Hao Zhao # 2 3 4,  Ke Sun 5,  Dan Deng 6,  Guanyu Liu 1,  Lan Li 1,  Tao Liu 1,  Lin Bao 1,  Wei Xu 7 8,  Chunying Chen 9
Affiliations

Affiliations

  • 1 New Cornerstone Science Laboratory, CAS Key Laboratory of Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, University of Chinese Academy of Sciences, Beijing, China.
  • 2 New Cornerstone Science Laboratory, CAS Key Laboratory of Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • 3 Chongqing Key Laboratory of Ultrasound Molecular Imaging, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China. [email protected].
  • 4 School of Medical Imaging, Changsha Medical University, Changsha, China. [email protected].
  • 5 Chongqing Key Laboratory of Ultrasound Molecular Imaging, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 6 School of Medical Imaging, Changsha Medical University, Changsha, China.
  • 7 Beijing Synchrotron Radiation Facility, Institute of High Energy Physics, Beijing, China.
  • 8 RICMASS, Rome International Center for Materials Science Superstripes, Roma, Italy.
  • 9 New Cornerstone Science Laboratory, CAS Key Laboratory of Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 41839838 DOI: 10.1038/s41392-026-02607-6
Abstract

Pyroptosis, which rapidly releases cellular contents through pyroptotic pores, is an ideal method for inducing in situ Cancer vaccines, evoking systemic antitumor immunity, and suppressing primary and metastatic tumors. However, the clinical translation of pyroptosis-based therapy is hindered by the inability to spatially control the activation of inert precursors and the inefficient catalytic activity of nanozymes, which often fail to generate sufficient Reactive Oxygen Species for effective treatment. To address this, we designed a conductive coordination nanozyme prodrug, Cu-DHN. Its π-conjugated polyphenol backbone functions as an intrinsic "electron highway," enabling rapid electron shuttling to utilize the entire nanoparticle volume for catalysis, thereby achieving exceptional peroxidase-like activity. Upon systemic administration, Cu-DHN remains inert in circulation but is precisely activated within the tumor microenvironment by a tandem GSH-depletion and H2O2-responsive logic gate. This triggers a self-cascade reaction that locally transforms the coordinated prodrug into juglone, which concurrently reverses gasdermin D epigenetic silencing and activates the NLRP3 inflammasome for caspase-1-mediated cleavage. This single-agent, tumor-specific initiation of Pyroptosis, augmented by concomitant Cuproptosis, elicits potent immunogenic cell death and robust systemic antitumor immunity, effectively suppressing primary and metastatic tumors while exhibiting a pristine safety profile. Our work establishes electron-shuttling coordination Polymers as a versatile platform for developing safe and potent catalytic immunotherapies.

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